tbuckley/cabot-search huggingface dataset:
Association between physical activity, immune-related adverse events, and mortality in patients undergoing immune checkpoint inhibition.
Authors: Rik Jasper Verheijden, Anna Cabane Ballester, Mick JM van Eijs, Anne SR van Lindert, Karijn Suijkerbuijk, Anne Maria May
Journal: Journal of Clinical Oncology (2023)

2643 Background: Immune checkpoint inhibitors (ICIs) have improved prospects for some, but not all patients with cancer and frequently induce severe immune-related adverse events (irAEs). While physical activity (PA) has been associated with prolonged survival and diminished toxicity of chemotherapy, its association with ICI efficacy and toxicity is currently unknown. Hence, here we study the association between PA in patients undergoing ICI, and survival and severe irAE occurrence. Methods: Patients with advanced cancer receiving anti-PD-(L)1 based immunotherapy at our academic center were enrolled in the UNICIT cohort. All participants who completed the PA questionnaire (SQUASH) at ICI initiation between 10-2019 and 01-2022 were included in this study. PA was quantified by calculating Metabolic Equivalent Task (MET) hours per week and moderate to vigorous sport and leisure time activity. Association of PA with overall survival (OS) was assessed using Cox proportional hazard regression. Association of PA with occurrence of a severe irAE (grade 3 or higher) within one year was assessed using logistic regression in patients with at least one year follow-up. All analyses were adjusted for sex, age, tumor type, treatment intent and ICI type. Results: In total, 251 patients were included, with a median follow-up of 20 months and a median age of 64 years. The majority (153 patients) had melanoma. Median OS was not reached. Compared to low levels of total PA, intermediate and high levels of total MET-hours were associated with prolonged survival (adjusted hazard ratios: 0.56 (95%CI 0.31-1.02) and 0.47 (95%CI 0.26-0.86), respectively; table). Thirty eight out of 209 patients with at least one year of follow-up developed severe irAEs within the first year. Compared to patients with low total PA levels, patients with intermediate or high levels of total PA have a lower odds of developing severe irAEs (adjusted odds ratios: 0.35 (95%CI 0.12-0.90) and 0.19 (95%CI 0.06-0.56), respectively). Similar trends of prolonged OS and reduced odds of severe irAE occurrence were observed in patients who performed more moderate to vigorous sport and leisure time activity. Conclusions: Higher physical activity levels at start of ICI treatment are associated with prolonged survival and lower risk of severe irAEs. Future research needs to elucidate whether inactive patients benefit from increasing PA levels after diagnosis. [Table: see text]
Novel LTK fusions based on NGS sequencing data in Chinese patients with solid tumors.
Authors: Hui Chen, Shaohua Yuan, Xiaoliang Shi, Fei Pang
Journal: Journal of Clinical Oncology (2023)

3144 Background: Leukocyte receptor tyrosine kinase ( LTK) gene has the same kinase domain (PTKc_ALK_LTK) as ALK, and could functionally response to ALK inhibitors such as lorlatinib. Previous study reported that CLIP1-LTK fusion was a novel oncogenic driver mutation in lung cancer (occur in 0.4% of non-small cell lung cancer), which was sensitive to the ALK tyrosine kinase inhibitor lorlatinib. So far, LTK fusion has been rarely reported. Methods: A total of 11 Chinese solid tumor patients were reviewed, including 6 cases of LTK positive rearrangements in DNA and 5 cases of LTK positive fusion in RNA. FFPE samples were collected for NGS-based 450 cancer gene panel detection in both DNA and RNA level, and matched blood samples were used as normal control to filter out germline mutations. LTK fusions were analyzed by OrigiFus algorithm. Results: We found 6 patients with LTK rearrangements by DNA-based NGS detection, including lung adenocarcinoma, colorectal cancer, stomach cancer, spindle cell sarcoma of small intestine, adenocarcinoma of the pancreas, and cancer of unknown primary, and 5 soft tissue sarcoma patients with RPAP1 E25- LTK E2 fusions by RNA-based NGS detection. We analyzed the patterns of partner genes and breakpoints of the 6 LTK rearrangements. The partner genes included NUSAP1 (n=2), NDUFAF1 (n=1), LOC105370802 (n=1), EHD4 (n=1), and AGBL1 (n=1). All these partner genes were located on the same chromosome as LTK, rather than CLIP1, which was identified as a translocation. The breakpoints on LTK included exon20 (n=2), intron1 (n=2), exon6 (n=1), and exon10 (n=1). Five of the 6 fusions consisted of a complete PTKc_ALK_LTK domain. Among the 6 LTK rearrangements, LTK E20- NUSAP1 E2 was predicted as a fusion. Interestingly, this clinical real-world sample also harbored a classic NTRK1 fusion, LMNA E2- NTRK1 E11. The other NUSAP1- LTK was predicted to have a transcript of 3’-3’, but one of the breakpoints was observed at LTK exon6, which could be located at the kinase domain, so the possibility of eventual fusion cannot be excluded. The two NUSAP1-LTK fusions were found in a stomach tumor and a soft tissue sarcoma, respectively. One non-small-cell lung cancer (NSCLC) patient had a breakpoint detected on LTK exon10, which is the same as the exon of CLIP1- LTK reported. Conclusions: This study revealed novel LTK fusions/rearrangements and their cancer distribution in Chinese patients with solid tumors. We gave the details of these fusions/rearrangements which enrich our understanding of the LTK fusion. Although the small number of cases, our analysis promoted the attention on LTK and its potential value of drug research and clinical treatment in pan-cancer.
A phase 2 basket trial of an ERK1/2 inhibitor (LY3214996) in combination with abemaciclib for patients whose tumors harbor pathogenic alterations in <i>BRAF</i>, <i>RAF1</i>, <i>MAP2K1/2</i> <i>ERK1/2</i>, and <i>NF1</i>.
Authors: Fadi Taza, Greg Andrew Durm, Mateusz Opyrchal, Shadia Ibrahim Jalal, Milan Radovich, Bryan P. Schneider, Anita Ahmed Turk
Journal: Journal of Clinical Oncology (2023)

e15088 Background: LY3214996 (L) is a potent inhibitor of ERK1/2 kinases that can potentially obviate resistance mechanisms in cancers that harbor BRAF, RAS, NF1, MAP2K1/2, and other MAPK alterations. Abemaciclib (A) is a CDK 4/6 inhibitor. Studies have shown that concomitant inhibition of the MAPK pathway exemplified by ERK inhibitors may augment the antitumor activity of CDK4/6 inhibitors. In this biomarker-informed phase 2 study, we assess the clinical efficacy of L in combination with A. Methods: The study enrolled patients with advanced unresectable or metastatic cancer with no other standard of care options available. The malignancy must harbor pathogenic alterations in BRAF, RAF1, MAP2K1/2, ERK1/2, or NF1, in whom standard treatments failed to provide clinical benefit. L was administered at a dose of 200 mg orally QD in combination with A at 150 mg BID hours on Days 1 through 28 of a 28-day cycle until progression, toxicity, or withdrawal. The primary endpoint is the objective response rate. Secondary outcomes include evaluation of safety and tolerability, progression-free survival (PFS), and duration of the overall response. Additionally, tumor samples were collected for organoid development. Results: Between September 1, 2020, and February 1, 2023, 12 patients were enrolled. Primary malignancies included colorectal (6), lung (1), breast (2), pancreas (1), uterus (1), and thyroid (1). The pathogenic alterations included NF1 (4), BRAF (6), and MAP2K1/2 (2). There were no CR or PR observed. Stable disease was achieved in 4 patients (33%) with a median disease control rate of 6.5 months. Pathogenic alterations in patients with stable disease included BRAF, MAP2K1/2, and NF1. Most common treatment-related adverse events of any grade included fatigue (41%), rash (41%), nausea (33%), vomiting (33%), anemia (25%), anorexia (25%), and increased creatinine (25%). There were no grade 4 or 5 adverse events. Conclusions: The combination of L+A is safe and promising in patients whose tumors harbor pathogenic alterations in BRAF, MAP2K1/2, and NF1. Enrollment is ongoing, and efficacy and toxicity outcomes continue to be assessed. (NCT04534283). Clinical trial information: NCT04534283 .
Comprehensive genomic analysis for homologous recombination deficiency in pancreatic cancer.
Authors: Kwangrok Jung, Jae Hyup Jung, Jinwoo Ahn, Bomi Kim, Jong-Chan Lee, Jaihwan Kim, Jin-Hyeok Hwang
Journal: Journal of Clinical Oncology (2023)

e15168 Background: Although homologous recombination deficiency (HRD) has been heavily studied in oncology, HRD in pancreatic cancer remains poorly understood beyond germline alterations in BRCA1, BRCA2 and PALB2. Methods: We performed whole exome sequencing (WES) on 205 patients with pancreatic cancer. Germline and somatic mutations in HRD genes were evaluated: (1) canonical HRD mutation ( BRCA1, BRCA2 and PALB2); and (2) non-canonical HRD mutation ( ATM, ATR, ATRX, CHEK2, BAP1, BARD1, BLM, BRIP1, NBN, RAD51 genes, RAD54 genes, FANC genes and ERCC genes). In addition, signature-based HRD classifiers were also applied: (1) the genomic instability score (GIS); (2) substitution base signature 3 (SBS3); and (3) small insertion and deletions 83B (ID83B). The frequency of HRD mutations and signatures-based HRD in pancreatic cancer were evaluated and their clinical utility were assessed by confirming the association with the response to platinum-containing chemotherapy. Results: Among the 205 patients, 41 patients (20.0%) were identified to harbor HRD mutations. Germline and somatic HRD mutations were identified in 19 (9.3%) and 24 (11.7%) patients, respectively. Mutations in canonical genes and non-canonical genes were found in 12 (5.9%) and 37 (18.1%) patients, respectively. Using signature-based HRD classifier, additional 45 (22.0%) patients were determined to be HRD. Among patients who received first-line FOLFIRINOX ( N = 113), canonical HRD mutation and signature-based HRD group showed higher response rate than non-canonical HRD and non-HRD group (75.0% and 57.1% vs. 31.3% and 33.3%, respectively). In the survival analysis of patients treated with FOLFIRINOX, canonical HRD and signature-based HRD group tended to have better overall survival than non-HRD group. Conclusions: Comprehensive genomic analysis could identify a significant number of HRD pancreatic cancer beyond germline BRCA1,2 and PALB2 mutation, and it would be helpful to choose the appropriate chemotherapy regimen.
Exploring the significance of PARP inhibitor therapy after first-line chemotherapy in patients with homologous recombination proficient ovarian cancer: An extracted individual patient data and trial-level meta-analysis.
Authors: Mateus Trinconi Cunha, Felippe Lazar Neto, Maria Del Pilar Estevez-Diz, Renata Colombo Bonadio
Journal: Journal of Clinical Oncology (2023)

5580 Background: The use of poly (ADP-ribose) polymerase inhibitors (PARPi) as maintenance therapy in advanced epithelial ovarian cancer (EOC) patients (pts) has shown to delay cancer progression among patients with mutated BRCA (mBRCA) or homologous recombination deficiency (HRD), with debatable and divergent benefit among the subgroup of patients with homologous recombination proficiency (HRP). We aimed to further clarify the efficacy of PARPi after first-line chemotherapy (1L CT) in patients with HRP EOC. Methods: A systematic literature search of PubMed, Embase, The Cochrane Library until February 9 th was conducted to identify articles or presentations of phase III clinical trials (P3CT) evaluating PARPi maintenance therapy after 1L CT in ovarian cancer. Individual patient data was reconstructed from Kaplan-Meier plots of progression-free survival (PFS) among pts with mBRCA, HRD and HRP through WebPlotDigitizer and R package IPDfromKM and futher combined. We also performed trial-level meta-analysis with a random effects model. Comparisons were made with Cox proportional hazards. Clinical benefit for each sub-group was accessed with the ESMO Magnitude of Clinical Benefit Formulary 2b (ESMO MBCS). Results: The literature search resulted in 513 items. After screening, 6 P3CT (SOLO1, PRIMA, VELIA, PAOLA, PRIME, and ATHENA-MONO) were selected, and the longer follow-up data of each trial was used. A total of 3205 pts were included in the analysis (2090 in PARPi arms, 1115 in control arms). HRP was associated with worse PFS regardless of the treatment arm (HRP vs mBRCA in PARPi arms: HR 1.92, 95% CI 1.62 – 2.21, P &lt; 0.001). Compared to control treatment arm, PARPi therapy was associated with a improved PFS in all subgroups, although the magnitude of benefit decreased from mBRCA to HRD and HRP (Table). Trial-level meta-analysis yielded similar results. PARPi therapy summed 4 out of 4 possible points at ESMO MBCS for mBRCA and HRD, but only 2 points among HRP pts, confirming a lower clinical benefit in this subgroup. Conclusions: This meta-analysis included additional P3CT recently presented and new data of subgroup analysis of previous studies. Results confirm a statistically significant benefit of PARPi maintenance after 1L CT for HRP EOC. Nevertheless, the relative and absolute gain in PFS is modest (9% in 2 years), while mBRCA and HRD subgroups have a substantial benefit. The worse prognosis of HRP pts, in addition to the small clinical benefit of PARPi therapy, highlights the need for new treatment strategies for this subgroup. [Table: see text]
Immune checkpoint inhibitor in high-risk oral potentially malignant disorders (IMPEDE study): An interim analysis on safety.
Authors: Andrea Alberti, Chiara Romani, Alberto Paderno, Simonetta Battocchio, Laura Ardighieri, Consuelo D'Ambrosio, Raul Pellini, Giorgio Peretti, Maria Cossu Rocca, Mohssen Ansarin, Paolo Boscolo Rizzo, Lorenzo Azzi, Giovanni Lodi, Carlo Gervasoni, Stefania Vecchio, Elena Bardellini, Alessandra Majorana, Cesare Piazza, Fabio Facchetti, Paolo Bossi
Journal: Journal of Clinical Oncology (2023)

2595 Background: Oral Potentially Malignant Disorders (OPMD) represent the most common oral precancerous condition, with a variable risk of malignant transformation. The most effective biomarker in predicting malignant transformation risk is loss of heterozygosity (LOH). Patients (pts) carrying OPMD with LOH at 3p14 and/or 9p21 plus LOH at another locus have an expected 3-year risk of developing oral cancer of 35%. This chromosomal profile is found in about 30% of OPMD. IMPEDE is a phase II, open-label, single-arm trial designed to evaluate the efficacy of PD-L1 inhibitor avelumab in reverting cancer transformation risk in OPMD with LOH. In this analysis, we report the first safety results, while data about treatment activity need longer follow up. Methods: During the screening period, pts undergo OPMD biopsy. If pathological diagnosis of dysplasia is confirmed, LOH valuation is performed and in case of positivity of this biomarker, subjects receive a short course of immunotherapy with avelumab 800 mg every 2 weeks for 4 total administrations. Follow-up after last avelumab dose is performed monthly and adverse event data are collected at every visit. Six months after treatment start, surgery and LOH re-assessment are performed. Results: Between November 2020 and December 2022, 49 pts were screened in 8 Italian centers. Of these, 16 pts (33%) had a LOH and 12 received the treatment (3 males, median age 65.5 years, range 49-81). Nine out of 12 treated patients had a previous oral cancer. After a median follow up of 14 months, 39 adverse events (AE) of any grade were reported, of these 18 were considered as immune related AEs (irAE). The most frequent AEs was grade 1 (G1) oral pain (4/12 pts), managed with local painkillers. Only three G2 irAEs were reported, namely amylase/lipase increase, psoriasis and fever. No grade 3-4 AEs were described, and no patient had to stop immunotherapy because of toxicities. Local excision after immunotherapy was not delayed by any treatment toxicities. Conclusions: This is the first trial with immunotherapy in an enriched population of OPMD selected according to LOH. First results support the feasibility of this approach, showing that immunotherapy with avelumab is safe and does not compromise subsequent local surgery. Clinical trial information: NCT04504552 .
Pembrolizumab, radiotherapy, and chemotherapy in neoadjuvant treatment of malignant esophago-gastric diseases (PROCEED): Assessment of pathologic response and toxicity in a prospective, phase II single-arm trial.
Authors: Pooja Karukonda, Brian G. Czito, Eileen Duffy, Hope Elizabeth Uronis, Thomas A. D'Amico, John H Strickler, Donna Niedzwiecki, Christopher Willett, Manisha Palta
Journal: Journal of Clinical Oncology (2023)

4062 Background: A standard treatment paradigm for locally advanced, resectable, non-metastatic esophageal or gastric adenocarcinomas (EGA) is neoadjuvant chemoradiation (CRT) followed by surgery. Historical pathologic complete response (pCR) rates after CRT with carboplatin/paclitaxel in the CROSS trial are low at 23%. Efficacy of adjuvant immunotherapy has since been shown in this patient population. The main objectives of this trial were to investigate whether neoadjuvant CRT + pembrolizumab improves pCR compared to the historical control of CRT alone, and also determine the associated acute and post-surgical toxicity of this approach. Methods: Single-institution, prospective phase II trial (NCT03064490) evaluating the efficacy and safety of neoadjuvant pembrolizumab + CRT followed by adjuvant pembrolizumab in patients with locally advanced operable EGA. CRT (45 Gy/25 fractions with concurrent weekly carboplatin [AUC 2] and paclitaxel [50 mg/m 2 of BSA]) with 3 cycles of pembrolizumab was administered as neoadjuvant therapy. Patients also received 3 cycles of adjuvant pembrolizumab after surgical resection if they did not experience ≥Grade 3 (G3) toxicity during neoadjuvant treatment. Baseline characteristics were collected. Pathologic response was scored from 0-3 per tumor regression grading. The percentage of patients with pCR (score of 0) are described. Acute toxicities are defined per CTCAE v4 and include relevant events occurring within 90 days after treatment. Results: Accrual is complete, with 35 patients with cT2-3N0-2M0 EGA enrolled from 10/10/2017-10/07/2022. 28/32 patients have completed neoadjuvant therapy and surgical resection. 89% of enrolled patients are male, and 94% are white. 97% have an esophageal primary, and 97% underwent R0 resection. 10/28 (35.7%: 95% CI: 17%, 53%) patients achieved a pCR. 22/32 patients have experienced treatment-related ≥G3 non-hematologic toxicity to date (94.2% G3, 5.8% G4). 18 patients experienced ≥G3 toxicity related to neoadjuvant therapy, with 53 events overall, the majority being GI (24.5%) or metabolic/nutritional disorders (24.5%). 10 patients experienced ≥G3 toxicity related to surgery, with 16 events overall, the majority being procedural complications (31.3%) and infectious disorders (31.3%). Conclusions: Patients undergoing neoadjuvant CRT + pembrolizumab for EGA experienced higher rates of pCR and acceptable rates of treatment-related toxicity compared to historical controls. This phase II trial demonstrates the safety and efficacy of this treatment paradigm, which warrants assessment in future prospective studies. Clinical trial information: NCT03064490 .
The significance of mucin on rectal MRI in patients with locally advanced rectal cancer being considered for watch-and-wait after neoadjuvant therapy.
Authors: Sean Judge, Parisa Malekzadeh, Marina J Corines, Marc J Gollub, Natally Horvat, Leonard B. Saltz, Andrea Cercek, Paul Bernard Romesser, Christopher H Crane, Iris H Wei, Maria Widmar, Emmanouil Pappou, Garrett Michael Nash, Jesse Joshua Smith, Philip Paty, Julio Garcia-Aguilar, Martin R. Weiser
Journal: Journal of Clinical Oncology (2023)

3614 Background: Neoadjuvant therapy (NAT) leads to a clinical complete response (cCR) in a significant proportion of patients with locally advanced rectal cancer (LARC) allowing for possible non-operative management. Along with physical exam and proctoscopy, magnetic resonance imaging (MRI) is used to evaluate for residual tumor following NAT. The presence of mucin on MRI leads to uncertainty about residual disease and appropriateness of watch-and-wait strategy (WW) in patients with no evidence of disease on proctoscopy (endoscopic cCR). We set out to determine the impact of radiographic mucin in patients with LARC after NAT. Methods: MRI reports between July 2016 to January 2020 at Memorial Sloan Kettering Cancer Center were queried for the presence of mucin in the tumor bed on post-treatment rectal MRI in patients with LARC following NAT. The clinicodemographic, pathologic, and outcomes data from these patients were compiled and analyzed. Results: Seventy-one patients were included in the final analysis who fit the pre-specified inclusion criteria (Table). Of the 71 patients with mucin present on post-treatment MRI, 19 patients (27%) entered a watch-and-wait (WW) strategy and 52 patients (73%) were planned for surgery (non-WW). Comparing the WW and non-WW cohorts, there was no difference in age, sex, clinical nodal status, or neoadjuvant regimen. Patients entering a WW protocol had a higher proportion of cT1-T2 tumors (32%) compared to non-WW (4%) (P &lt; 0.01). All WW patients had endoscopic cCR, while only one non-WW patient achieved endoscopic cCR. Of 52 non-WW patients, 49 underwent resection and 3 did not have surgery due to disease progression. The pathologic complete response (pCR) rate in the non-WW patients who underwent surgery was 10%. Of 19 WW patients, 4 experienced regrowth (21%), while 15 (79%) have no local regrowth, with a median follow up of 4.2 years (range 2.4-6.3 yrs). Two patients (11%) experienced distant failure. Conclusions: The presence of mucin after NAT for LARC should not necessarily preclude a WW strategy in otherwise appropriate candidates who achieve an endoscopic cCR. [Table: see text]
CDK4/6 inhibitors and cardiovascular toxicity: Real-world evidence.
Authors: Oraianthi Fiste, Michael Liontos, Maria Gavriatopoulou, Constantine Dimitrakakis, George Evangelou, Vasiliki Nikolaidou, Elias A. Kotteas, Kostas N. Syrigos, Meletios A. Dimopoulos, Flora Zagouri
Journal: Journal of Clinical Oncology (2023)

e15074 Background: Cyclin-dependent kinases 4/6 inhibitors (CDK4/6i) have fundamentally transformed the therapeutic landscape of hormone receptor-positive and human epidermal growth factor receptor 2 (HER2) negative breast cancer, either as monotherapy (abemaciclib) or combined with classic endocrine therapy (ribociclib, abemaciclib, and palbociclib). However, evidence regarding treatment-related cardiovascular complications, beyond the context of clinical trials, remains scarce. Methods: We retrospectively explored the FDA Adverse Events Reporting System (FAERS) to gain insight into both frequency and spectrum of cardiovascular toxicities of these novel targeted agents in real-world setting. Results: For the period January 2018 - September 2022, a total of 90,999 adverse events (AEs) in patients under CDK4/6i have been reported, with 2,739 (3.01%) and 5,176 (5.69%) records being submitted as cardiac and vascular events, respectively. The incidence of these AEs was higher in the case of ribociclib, with arrhythmia representing the main cardiac complication (512 cases), followed by palpitations (120 cases), and acute coronary syndrome (115 cases). Interestingly, there was only one report of QT prolongation; of note, ribociclib has labeling guidance for QTc assessment. Hypertension/hypertensive crisis (302 cases), flushing (251 cases), and thrombotic events (226 cases) -with the exception of pulmonary embolism which was categorized as respiratory AE- comprised the foremost vascular toxicities associated with ribociclib. Conclusions: FAERS displays a public, post-market safety evaluation database with reports from healthcare professionals as well as consumers, yet it may include duplicates, inaccurate information, and fails to confirm causal relationship between the AEs and the medicinal product. In the light of CDK4/6i long-term usage, pharmacovigilance studies are warranted to elucidate their potential cardiovascular hazard. [Table: see text]